ABSTRACT The mission of the Cancer Immunology (CI) Program is to understand the basic biology of the immune response to cancer and to use those data to optimize immunotherapy for cancer?first in preclinical models, and subsequently through the design and execution of cutting-edge translational clinical trials. The Program, formerly led by Drew Pardoll, M.D., Ph.D., and Elizabeth Jaffee, M.D., is now led by Dr. Pardoll and Charles Drake, M.D., Ph.D., as Dr. Jaffee assumed the role of Deputy Director of the Sidney Kimmel Comprehensive Cancer Center (SKCCC). The Program includes 21 members from seven departments within the Johns Hopkins University School of Medicine. National Cancer Institute (NCI) and other peer-reviewed support of Program members totals $8.9 million total costs annually, and the Program receives an additional $26.1 million annually in nonpeer-reviewed funding. Sixteen members have peer-reviewed funding. The total number of publications by Program members is 434, of which 108 (25%) were Intra-Programmatic, 188 (43%) were Inter- Programmatic and 142 (33%) were multi-institutional collaborations. Building on basic, translational and clinical trials successes over the past five years, the Program seeks to harvest the untapped capacity of the immune system's power to provide further durable cancer remission and even cure. The Programs aims are to: Aim 1: Continue to unravel basic mechanisms of immune regulation and cancer immunity that will fuel the next generation of cancer immunotherapies. Aim 2: Utilize appropriate preclinical models to understand and optimize antitumor immunity, including identification of the most potent combinatorial approaches, such as vaccines together with checkpoint inhibitors. Aim 3: Initiate and complete cutting-edge clinical trials, including the incorporation of appropriate translational biomarker studies designed to guide, with precision, current and next-generation immunotherapies. In particular, the Program will build on studies over the past five years identifying ligands in the tumor microenvironment (TME) and on tumor genetics and viral association as predictors of response to checkpoint blockade. These aims are facilitated by partnerships among laboratory-focused investigators, translational investigators in the CI Program and multiple other SKCCC Programs to jointly develop specific preclinical immunotherapy strategies and then translate them into the most suitable clinical settings. Notable advances over the past five years include 1) the preclinical testing and foundational clinical development of the first anti-PD-1 antibodies in cancer therapy, 2) development of the PD-L1 biomarker, 3) demonstration that mismatch repair deficiency (MMRd) cancers and virus-associated cancers have a very high response to anti-PD-1, 3) demonstration of patient benefit with novel prime-boost vaccine strategies in pancreas cancer, 4) development of marrow- infiltrating lymphocytes for adoptive cell therapy, 5) discovery of four novel immune checkpoint pathways, 6) development of a novel vaccine platform (STINGVAX), and 7) discovery of metabolic pathways that modulate T cell function and enhance antitumor efficacy.